Apremilast is a phosphodiesterase 4 (PDE4) inhibitor. Apremilast is chemically known as N-[2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl) ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide. Apremilast is indicated for the treatment of adult patients with active psoriatic arthritis. It is available under the trade name of OTEZLA® as an inhibitor of phosphodieasterase 4 (PDE4) and OTEZLA tablets are supplied in 10, 20, and 30 mg strengths for oral administration.
U.S. Pat. No. 6,020,358 discloses racemic 2-[1-(3-ethoxy-4-methoxy phenyl)-2-(methylsulfonyl)ethyl]-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]acetamide and process for its preparation, which is incorporated herein by reference.
U.S. Pat. No. 7,427,638 discloses stereomerically pure (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione, substantially free of its (−) isomer, or a pharmaceutically acceptable metabolite, salt, solvate or hydrate, thereof and its pharmaceutical composition.
International PCT application number WO2009120167 disclose various solid forms including crystal forms and amorphous forms and their mixture comprising one or more of the Forms A, B, C, D, E, F, G and an amorphous solid form. WO2014072259 discloses pharmaceutical composition of amorphous Apremilast with at least one excipients prepared by melt extrusion technique.
CN104761484A discloses the new polymorphic form i.e., form: II.
CN104892486A discloses the new polymorphic form i.e., form: B+.
The present invention provides a process for the preparation of Apremilast using novel intermediates. The process of the present invention can be practiced on an industrial scale, and also can be carried out without sacrifice of overall yield.
The technical problem underlying the present invention is to circumvent the drawbacks of the known crystalline forms of Apremilast disclosed in the state of the art such as toxicity issues of solvates, stability issues of polymorphic forms due to conversation into the other form, bioavailability issues due to limited solubility and preparation issues due to similar crystallization processes; by providing novel polymorphic forms of Apremilast which shows high solubility and is obtained in polymorphically pure form in an easy and reliable manner.
The specific solvate and polymorphic form provided by the present invention possess superior, highly favourable properties appropriate for pharmaceutical development that were not disclosed in the prior art. Further, these solid state forms permit the preparation of pharmaceutical compositions with improved performance characteristics to be prepared.